The present invention relates to an improved method for increasing the target-specific toxicity of a chemotherapy drug by pretargeting an enzyme to a mammalian target site and administering a cytotoxic drug known to act at the target site, or a prodrug thereof, which drug is also detoxified to form an intermediate of lower toxicity using the mammal's ordinary metabolic processes, whereby the detoxified intermediate is reconverted to its more toxic form by the pretargeted enzyme and thus has enhanced cytotoxicity at the target site. Where a prodrug is used, a further improvement is achieved by targeting a second enzyme to the target site that converts the prodrug to the active drug. Use of versatile bispecific antibodies that can bind more than one kind of enzyme to the target site facilitates efficient enzyme loading and further amplification of the target-specific activity.
It is a continuing aim of chemotherapy to deliver a higher total dose of chemotherapeutic to a tumor target, and/or lower doses to sensitive non-target tissues. Direct attachment of drugs to specific targeting agents such as monoclonal antibodies (MAbs) has a number of drawbacks, including diminishing a drug's potency and changing the pharmacokinetic properties of the MAb for the worse. Despite this, impressive results have been seen in preclinical animal results using conjugates of MAbs and standard chemotherapy drugs such as doxorubicin (Trail et al., Science 261:212-215, 1993 & Cancer Res., 57:100-105, 1997). A further problem in translating good animal results to the human situation is that in the latter, tumor target uptake of MAbs is often two to four orders of magnitude lower on a percent injected dose per gram basis.
In part to circumvent the above problems a novel approach was tried whereby an antibody enzyme conjugate was administered, followed sometime later by a precursor of an active drug, i.e. a prodrug. The enzyme localized to target by the tumor-specific antibody would act on the prodrug to release active drug at the target. The method has the advantages of not requiring coupling of drug to MAb, and by virtue of targeted enzyme activity the ability to produce large amounts of drug where it is needed. The latter advantage can overcome the issue of low absolute tumor accretion of MAbs in humans.
In a further modification, a binary system for targeting prodrugs using a bispecific monoclonal antibody (bsMAb) was described by Hansen U.S. Ser. No. 08/445,110 (hereinafter, “Hansen '110”), the disclosure of which is incorporated herein in its entirety by reference. in this system, a bsMAb with an anti-target arm and an anti-enzyme arm is given, followed later by an enzyme, e.g., glucuronidase, which is thus targeted to the disease site. Later still, a prodrug, e.g., a glucuronide prodrug, is administered and the free drug released by the tumor-targeted enzyme. In addition to addressing the issue of low levels of MAb accretion at human tumors, this method has the further advantage of not requiring the coupling of relatively large MAb and enzyme structures, both of whose activities and pharmacokinetic properties can be affected adversely by such conjugations.
One limitation of the bsMAb/prodrug invention as outlined above is the need for a specific antibody directed toward a specific enzyme. Thus, its adoption with different combinations of prodrugs and enzymes would require the preparation of new bsMAbs for each combination.
A need therefore continues to exist for a method for increasing the target-specific toxicity of a chemotherapy drug which is detoxified by normal metabolic processes to form an intermediate of lower toxicity, whereby the detoxified intermediate is reconverted to its more toxic form by the pretargeted enzyme and thus, has enhanced cytotoxicity at the target site.